APP-dependent up-regulation of Ptch1 underlies proliferation impairment of neural precursors in Down syndrome

Abstract

Mental retardation in Down syndrome (DS) appears to be related to severe neurogenesis impairment during critical phases of brain development. Recent lines of evidence in the cerebellum of a mouse model for DS (the Ts65Dn mouse) have shown a defective responsiveness to Sonic Hedgehog (Shh), a potent mitogen that controls cell division during brain development, suggesting involvement of the Shh pathway in the neurogenesis defects of DS. Based on these premises, we sought to identify the molecular mechanisms underlying derangement of the Shh pathway in neural precursor cells (NPCs) from Ts65Dn mice. By using an in vitro model of NPCs obtained from the subventricular zone and hippocampus, we found that trisomic NPCs had an increased expression of the Shh receptor Patched1 (Ptch1), a membrane protein that suppresses the action of a second receptor, Smoothened (Smo), thereby maintaining the pathway in a repressed state. Partial silencing of Ptch1 expression in trisomic NPCs restored cell proliferation, indicating that proliferation impairment was due to Ptch1 overexpression. The overexpression of Ptch1 in trisomic NPCs resulted from increased levels of AICD [a transcription-promoting fragment of amyloid precursor protein (APP)] and increased AICD binding to the Ptch1 promoter. Our data provide novel evidence that Ptch1 overexpression underlies derangement of the Shh pathway in trisomic NPCs with consequent proliferation impairment. The demonstration that Ptch1 overexpression in trisomic NPCs is due to an APP fragment provides a link between this trisomic gene and the defective neuronal production that characterizes the DS brain.

Altered neurogenesis in mouse models of Alzheimer disease

“…A combination of environmental enrichment and enhanced physical exercise starting in young mice resulted in a strongly increased neurogenesis rate in the dentate gyrus comparable to that of euploid mice. 42 In addition to an increased gene dose of full-length APP, levels of fragments derived from proteolytical APP processing are also elevated in Ts65Dn mice 43 and likely also in mouse models with APP overexpression. A normalization of the triplicated APP expression using APP shRNA lentiviral particles led to a restoration of neuronal maturation and differentiation and increased neuriteoutgrowth to normal levels in a dose-dependent manner.…”

“…Trisomic neural precursor cells derived from Ts65Dn mice have been demonstrated to exhibit increased expression levels of the Shh receptor Ptch1, resulting in suppression of Smoothend (Smo), a second receptor involved in this signaling pathway. 43 Elevated AICD levels, and therefore increased AICD binding to the Ptch1 promotor, resulted in Ptch1 overexpression while Ptch1 silencing using antisense oligonucleotides lead to a restoration of cell proliferation in trisomic neural precursor cells. 43 In support of this observation, a recent study has been demonstrated that g-secretase inhibitor treatment normalized AICD levels and restored impaired neurogenesis and Sonic Hedgehog signaling in Ts65Dn-derived neurospheres.…”

“…43 Elevated AICD levels, and therefore increased AICD binding to the Ptch1 promotor, resulted in Ptch1 overexpression while Ptch1 silencing using antisense oligonucleotides lead to a restoration of cell proliferation in trisomic neural precursor cells. 43 In support of this observation, a recent study has been demonstrated that g-secretase inhibitor treatment normalized AICD levels and restored impaired neurogenesis and Sonic Hedgehog signaling in Ts65Dn-derived neurospheres. 50 The crucial role of AICD is underscored by an agedependent decrease in BrdU incorporation and DCX-immunoreactive cells in the dentate gyrus of AICD transgenic mice.…”

Early-occurring proliferation defects in peripheral tissues of the Ts65Dn mouse model of Down syndrome are associated with patched1 over expression

“…Neural precursor cells from the subventricular zone (SVZ) of Ts65Dn mice exhibit a higher expression of the sonic hedgehog (Shh) receptor patched1 (Ptch1). 13 Ptch1 exerts a negative effect on the membrane receptor smoothened (Smo). Smo is responsible for activating the downstream element of the Shh pathway, thereby stimulating cell proliferation.…”

“…Our group has previously shown that the increased expression of Ptch1 in neural precursors of trisomic mice is due to an excessive formation of amyloid precursor protein intracellular domain, a soluble fragment of amyloid precursor protein (APP). 13 As APP is a trisomic gene, its over expression may also cause an increased expression of Ptch1 in peripheral tissues, which, in turn, may reduce proliferation potency.…”